3-aryl-2-hydroxypropionic acid derivative (I)

ABSTRACT

A novel 3-aryl-2-hydroxypropionic acid derivative, a process and intermediate for its manufacture, pharmaceutical preparations containing it and the use of the compound in clinical conditions associated with insulin resistance.

FIELD OF INVENTION

The present invention releates to a novel 3-aryl-2-hydroxypropionic acidderivative, to a process and intermediate for preparing such a compound,having the utility in clinical conditions associated with insulinresistance, to methods for its therapeutic use and to pharmaceuticalcompositions containing it.

BACKGROUND OF THE INVENTION

Insulin resistance, defined as reduced sensitivity to the actions ofinsulin in the whole body or individual tissues such as skeletal muscle,myocardium, fat and liver prevail in many individuals with or withoutdiabetes mellitus. The insulin resistance syndrome, IRS, refers to acluster of manifestations including insulin resistance with accompanyinghyperinsulinemia, possibly non insulin dependent diabetes mellitus(NIDDM); arterial hypertension; central (visceral) obesity; dyslipidemiaobserved as deranged lipoprotein levels typically characterized byelevated VLDL (very low density lipoproteins) and reduced HDL (highdensity lipoproteins) concentrations and reduced fibrinolysis.

Recent epidemiological research has documented that individuals withinsulin resistance run a greatly increased risk of cardiovascularmorbidity and mortality, notably suffering from myocardial infarctionand stroke. In non-insulin dependent diabetes mellitus theseatherosclerosis related conditions cause up to 80% of all deaths.

In clinical medicine there is at present only limited awareness of theneed to increase the insulin sensitivity in IRS and thus to correct thedyslipidemia which is considered to cause the accelerated progress ofatherosclerosis.

Furthermore there is at present no pharmacotherapy available toadequately correct the metabolic derangements associated with IRS. Todate, the treatment of NIDDM has been focused on correction of thederanged control of carbohydrate metabolism associated with the disease.Stimulation of endogenous insulin secretion by means of secretagogues,like sulphonylureas, and if necessary administration of exogenousinsulin are methods frequently used to normalize blood sugar but thatwill, if anything, further enhance insulin resistance and will notcorrect the other manifestations of IRS nor reduce cardiovascularmorbidity and mortality. In addition such treatment involves asignificant risk of hypoglycemia with associated complications.

Other therapeutic strategies have focused on aberrations in glucosemetabolism or absorption, including biguanides, such as methformin, orglucosidase inhibitors, such as acarbose. Although these agents havebeen efficacious to a degree, their limited clinical effect isassociated with side effects.

A novel therapeutic strategy involves the use of insulin sensitizingagents, such as the thiazolidinediones, which, at least in part, mediatetheir effects via an agonistic action on nuclear receptors. Ciglitazoneis the prototype in this class. In animal models of IRS these compoundsseem to correct insulin resistance and the associatedhypertriglyceridaemia and hyperinsulinemia, as well as hyperglycemia indiabetes, by improving insulin sensitivity via an effect on lipidtransport and handling, leading to enhanced insulin action in skeletalmuscle, liver and adipose tissue.

Ciglitazone as well as later described thiazolidinediones in clinicaldevelopment either have been discontinued reportedly due to unacceptabletoxicity or show inadequate potency. Therefore there is a need for newand better compounds with insulin sensitizing properties.

PRIOR ART

Compounds of the Formula

and certain derivatives thereof disclosed in U.S. Pat. No. 5,306,726 andWO 91/19702 are said to be useful as hypoglycemic andhypocholesterolemic agents, and in U.S. Pat. No. 5,232,945 said to beuseful in the treatment of hypertension.

AU 650 429 discloses structurally related compounds, but claimed to havedifferent properties: diuretic, antihypertensive, plateletsanti-aggregating and anti-lipoxygenase properties.

EP 139 421 discloses compounds having the ability to lower blood lipidand blood sugar levels. Among these compounds is troglitazone, acompound that has reached the market for treatment of NIDDM or decreasedglucose tolerance.

DESCRIPTION OF THE INVENTION

It has now surprisingly been found that the novel compound(S)-2-ethoxy-3-[4(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid having the formula I

is effective in conditions associated with insulin resistance.

The invention also relates to pharmaceutically acceptable salts,solvates, such as hydrates, and crystalline forms of the compound of theformula I.

In the present specification the expression “pharmaceutically acceptablesalts” is intended to define but is not limited to such salts as thealkali metal salts (e.g. sodium, lithium and potassium), alkaline earthmetal salts (e.g. calcium, barium and magnesium), aluminium, zinc andbismuth salts, ammonium salts, salts with basic amino acids, such asarginine, lysine, and salts with organic amines such as ethanolamine,ethylenediamine, triethanoleamine, benzylphenethylamine, diethylamine,tromethamine, benzathine, chloroprocaine, choline, meglumine, procaine,clemizole and piperazine.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all pharmaceutically acceptable saltsthereof, crystalline forms and solvates thereof such as for instancehydrates.

Methods of Preparation

The compound of the invention may be prepared as outlined belowaccording to any of methods A-H. However, the invention is not limitedto these methods, the compounds may also be prepared as described forstructurally related compounds in the prior art.

A. The compound of the invention of the formula I, can be prepared byconverting a compound of formula II

wherein A is —OR^(p), wherein R^(p) is a protective group, e.g. ethyl,or A is a chiral auxiliary group, such as a chiral amine, erg.(R)-fenylglycinol, a chiral alcohol, such as menthol or a chiraloxazolidinone, such as (S)-4-benzyl-2-oxazolidinone. The convertion canbe performed as a hydrolysis which can be either acidic or basic andperformed according to standard methods known to anyone skilled in theart or as described in the experimental part.

B. The compound of the formula I or the formula II, wherein A is achiral auxiliary group or —OR^(p) and R^(p) is as defined above, can beprepared by reacting a compound of the formula III

wherein X is OH or a leaving group such as a sulfonate or a halogen,with a compound of the formula IV

wherein Q is H and A is a chiral auxiliary group, —OH or —OR^(p) is asdefined above. The reaction can be performed either by an alkylationreaction or a Mitsunobu reaction.

In an alkylation reaction the leaving group X can be a sulfonate such asmesylate, nosylate, tosylate, or a halogen, such as bromine or iodine.The compounds of formula III and IV, in approximately equimolar amountsor with an excess of either compound, are heated to reflux temperaturein an inert solvent, such as isopropanol or acetonitrile, in thepresence of a base, such as potassium carbonate or cesium carbonate.

The mixture is refluxed for the necessary time, typically between 0.5 hto 24 h, the work up procedure usually includes filtration, for removalof solid salt, evaporation, neutralisation (when A=OH) and extractionwith water and an organic solvent such as dichloromethane, ethylacetate, or diethyl ether.

The crude product is purified if desired e.g. by recrystallization or bystandard chromatographic methods.

The Mitsunobu reaction can be carried out according to standard methodsor as described in for example Tsunoda T., Yamamiaya Y., Ito S.,Tetrahedron Letters, 34, 1639-1642 (1993) or O. Mitsunobu, Synthesis,1981, p.1. When using a Mitsunobu reaction A can not be —OH.

In a typical Mitsunobu reaction a compound of formula III, wherein thegroup X is a hydroxyl group, and a compound of formula IV are mixed, inapproximately equimolar amounts or with an excess of either compound, inan inert solvent, such as chloroform, dichloromethane, ortetrahydrofuran. A slight molar excess, 1-4 equivalents, of anazodicarboxylate, such as DEAD or ADDP and a phosphine (1-4equivalents), such as tributylphosphine or triphenylphosphine are addedand the reaction is stirred at a temperature high enough—for exampleroom temperature—and a time long enough (1-24 hours) to obtain product,which can be worked up with standard literature methods and if desiredpurified, e.g. by standard chromatographic methods.

The compound of formula III can be prepared by standard procedures knownto anyone skilled in the art, from commercially available startingmaterials or as described in the experimental section.

The compound of formula IV wherein Q is H and A is a chiral auxiliarygroup, —OH or —OR^(p), wherein R^(p) is as defined above, can beprepared as described below in the experimental part or by converting acompound of formula IV

wherein Q is R^(q), wherein R^(q) is a protective group, e.g. benzyl,and A is a chiral auxiliary group, —OH or —OR^(p) wherein R^(p) is asdefined above.

C. The compound of formula II, wherein A is a chiral auxiliary group,and the compound of formula IV, wherein A is a chiral auxiliary groupand Q is hydrogen or R^(q), wherein R^(q) is as defined above and, canbe prepared by diastereoisomeric separation of the compound of theformula V

wherein A is a chiral auxiliary group, Q is hydrogen,—CH₂CH₂Ph-4-OSO₂CH₃or R^(q), wherein R^(q) is as defined above. The separation of thediastereomers can be performed either by crystallization or bychromatography. The chromatographic separation can be performed asdescribed in the experimental part.

The compound of formula V wherein A is a chiral auxiliary group, Q ishydrogen, —CH₂CH₂Ph-4-OSO₂CH₃ or R^(q), wherein R^(q) is as definedabove, can be prepared by converting a compound of formula VI

wherein Q is hydrogen, —CH₂CH₂Ph-4-OSO₂CH₃ or R^(q), and R^(x) ishydrogen or R^(p), wherein R^(q) and R^(p) are as defined above, forexample by reacting it with a chiral amine or a chiral alcohol.

The compound of formula V when A is a chiral amine can be prepared byreacting a compound of formula VI with a chiral amine such as (R)-phenylglycinol for example in the presence of a peptide coupling system (e.g.EDC, DCC, HBTU, TBTU, PyBop or oxalylchloride in DMF), an appropriatebase (e.g. pyridine, DMAP, TEA or DiPEA) and a suitable organic solvent(e.g. dichloromethane, acetonitrile or DMF) in accordance to methodswell known to those skilled in the art or as described in the examples.

The compound of formula V when A is a chiral alcohol can be prepared inthe same way using a chiral alcohol, such as menthol, instead of achiral amine, or by the mix-anhydride method with pivaloyl chloride andthe lithium salt of the chiral alcohol.

The compound of formula V wherein A is a chiral auxiliary group and Q ishydrogen, —CH₂CH₂Ph-4-OSO₂CH₃ or R^(q), wherein R^(q) is as definedabove, and the compound of formula VI, wherein Q is hydrogen,—CH₂CH₂Ph-4-OSO₂CH₃ or R^(q) and R^(x) is hydrogen or R^(p), whereinR^(q) and R^(p) are as defined above, can be prepared by reduction of acompound of formula VII

wherein A is a chiral auxiliary group, —OH, or —OR^(p) wherein R^(p) isas defined above and Q is hydrogen, —CH₂CH₂Ph-4-OSO₂CH₃ or R^(q),wherein R^(q) is as defined above, and if desired followed by removal ofprotecting groups.

The reduction of the olefin may be carried out by using a wide varietyof reducing methods known to reduce carbon-carbon double bonds, such ascatalytic hydrogenation in the presence of an appropriate catalyst orhydrogen transfer reagents such asdiethyl-2,5-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.

The catalytic hydrogenation can be performed in alcohol, cellosolves,protic polar organic solvents, ethers, lower alifatic acids, andparticularly in methanol, ethanol, methoxyethanol, dimethylformamide,tetrahydrofuran, dioxane, dimetoxyethane, ethyl acetate or acetic acideither used alone or in mixture. Examples of the catalysts used includepalladium black, palladium on charcoal, platinum oxide or Wilkinson'scatalyst. This reaction can be performed at different temperatures andpressures depending on the reactivity of the aimed reaction.

In case of hydrogen transfer reaction withdiethyl-2,5-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate the reactioncan be conducted by mixing equimolar amounts of reactants and warmingthe mixture to melting (140-250° C.) in inert atmosphere or in vacuum.

The compound of formula VII wherein A is a chiral auxiliary group, —OH,or —OR^(p) wherein R^(p) is as defined above and Q is hydrogen,—CH₂CH₂Ph-4-OSO₂CH₃ or R^(q), wherein R^(q) is as defined above, can beprepared by a condensation reaction, such as a Knoevenagel or Wittigtype reaction, of a carbonyl compound of the formula VIII

wherein Q is hydrogen, —CH₂CH₂Ph-4-OSO₂CH₃ or R^(q), wherein R^(q) is asdefined above, with a compound of the formula IX

in which formula A is a chiral auxiliary group, —OH or —OR^(p), whereinR^(p) is as defined above, or a compound of the formula X

in which formula A is a chiral auxiliary group or —OR^(p), wherein R^(p)is as defined above, L¹═L²═L³ are phenyl or L¹═L² are —Oalkyl and L³ is═O, and, if desired, followed by removal of protecting groups or by anarylation reaction as described in for example Cacchi S., Ciattini P.G., Morera E., Ortar G., Tetrahedron Letters, 28 (28) 1987, pp3039-3042.

In the condensation step, approximately equimolar amounts of reactantsare mixed in the presence of a base, to provide the olefin compound.This step may be carried out in the presence of an inert solvent or inthe absence of a solvent at a temperature between −20° C. and themelting point for the mixture. It might be necessary to add adehydrating agent in order to achieve the olefinic compound.

In a typical such reaction the compounds of formula VIII and formula IXare mixed in a solvent such as tetrahydrofuran. Anhydrous potassiumtert-butoxide is slowly added at low temperature i.e. −20° C. Thereaction is quenched with acetic acid. The crude product is isolated,redissolved in toulene and refluxed with p-toluene sulfonic acid in aDean-Stark apparatus. The solution is cooled and the product is isolatedand purified according to standard methods (see Groger T., Waldmann E.,Monatsh Chem 89, 1958, p 370).

The condensation step could also be performed as a Wittig-type reaction(see for example Comprehensive Organic Synthesis Vol. 1 p. 755-781Pergamon Press) or as described in the experimental part.

In a typical such reaction, approximately equimolar amounts of reactantsof formula VIII and formula X are stirred in the presence of a base suchas tetramethylguanidine or potassium carbonate in a 1-5 fold molarexcess. This step may be carried out in the presence of an inert solventsuch as dichloromethane or acetonitrile and at a suitable temperature(−10° C.+60° C.) and at a time long enough.

The compound of the formula VIII when Q is —CH₂CH₂Ph-4-OSO₂CH₃ can beprepared by coupling a compound of the formula III wherein X is —OH or aleaving group such as a sulfonate or a halogen, with a compound of theformula XI

When X is a leaving group such as a sulfonate or a halogen, the reactionmay be performed as an alkylation reaction and when X is —OH, as aMitsunobu reaction as described above.

D. The compound of formula I or formula II wherein A is —OR^(p) andR^(p) is as defined above and the compound of formula IV wherein A is OHor —OR^(p) and Q is H or R^(q) wherein R^(p) and R^(q) are as definedabove can be prepared by enantiomeric separation, such as chiralchromatography of the compound of the formula V

wherein A is —OH or —OR^(p), Q is H, —CH₂CH₂Ph-4-OSO₂CH₃ or R^(q)wherein r^(p) and R^(q) are as defined above.

E. The compound of the formula I or the formula II wherein A is a chiralauxiliary group or —OR^(p), wherein R^(p) is as defined above, and thecompound of formula IV wherein A is a chiral auxiliary group, —OH, or—OR^(p), wherein R^(p) is as defined above and Q is hydrogen or R^(q),wherein R^(q) is as defined above and, can be prepared by asymmetricreduction of a compound of the formula VII

wherein A is a chiral auxiliary group, —OH, or —OR^(p), wherein R^(p) isas defined above and Q is hydrogen, —CH₂CH₂Ph-4-OSO₂CH₃ or R^(q),wherein R^(q) is as defined above. The asymmetric reduction can hecarried out using a wide variety of reducing methods known to reducecarbon-carbon double bonds such as catalytic hydrogenation in thepresence of an appropriate chiral catalyst such as Rh-BINAP or[Et-DuPHOS-Rh(COD)] or catalytic hydrogenation with an appropriatecatalyst, such as palladium on charcoal using the chiral auxiliary groupto induce the asymmetry.

The catalytic hydrogenation can be carried out in a wide variety ofsolvents, such as alcohol, cellosolves, protic polar organic solvents,ethers, lower alifatic acids, and particularly in methanol, ethanol,methoxyethanol, dimethylformamide, tetrahydrofuran, dioxane,dimetoxyethane, ethyl acetate or acetic acid, either used alone or in amixture. The reaction can proceed at different temperatures andpressures depending on the reactivity of the aimed reaction.

F. The compound of the formula I or the formula II, wherein A is achiral auxiliary group, or —OR^(p), wherein R^(p) is as defined above,and the compound of formula IV wherein A is a chiral auxiliary group,—OH, or —ORp, wherein R^(p) is as defined above and Q is hydrogen orR^(q), wherein R^(q) is as defined above, can be prepared by alkylatinga compound of the formula XII

wherein A is a chiral auxiliary group, —OH, or —OR^(p), wherein R^(p) isas defined above, and Q is hydrogen, —CH₂CH₂P-4-OSO₂CH₃ or R^(q),wherein R^(q) is as defined above, with the required stereochemistrydependent on the reaction conditions used.

The alkylation may be carried out using a variety of alkylating agents,such as ethyl halide or diethyl sulfate (see for example Benedict D. R.,Bianchi T. A., Cate L. A., Synthesis (1979), pp. 428-429, Barluenga J.,Alonso-Cires L., Campos P. J., Asensio G., Synthesis, 1983, p. 53-55,Bull Chem Soc Jpn, 1986, 59, 2481, S. Patai, The Chemistry of the EtherLinkage, Wiley-Interscience NY, 1967, 445-498 or Survey of OrganicSynthesis vol 1, Wiley-Interscience 1970, NY, p. 285-328).

The compound of formula XII wherein A is a chiral auxiliary group, —OH,or —OR^(p), wherein R^(p) is as defined above, and Q is hydrogen,—CH₂CH₂Ph-4-OSO₂CH₃ or R^(q), wherein R^(q) is as defined above, can beprepared by asymmetric reduction of a compound of the formula XIII

wherein A is a chiral auxiliary group, —OH, or —OR^(p), wherein R^(p) isas defined above, and Q is hydrogen, —CH₂CH₂Ph-4-OSO₂CH₃ or R^(q),wherein R^(q) is as defined above.

The asymmetric reduction may be performed by using a wide variety ofreducing methods which are known to reduce ketones enantioselectively(see Flynn G. A., Beight D. W., Tetrahedron Letters, 29(4), 1988, pp.423-426).

The compound of formula XII wherein A is a chiral auxiliary group and Qis hydrogen, CH₂CH₂Ph-4-OSO₂CH₃ or R^(q), wherein R^(q) is as definedabove, may also be prepared by induced chiral reduction of a compound offormula VIII, wherein A is a chiral auxiliary group and Q is hydrogen,—CH₂CH₂Ph-4-OSO₂CH₃ or R^(q), wherein R^(q) is as defined above (seeXiang Y. B., Snow K., Belley M., J. Org. Chem., 1993, 58, pp 993-994).

The compound of formula XII, wherein A is a chiral auxiliary group, —OHor —OR^(p), wherein R^(p) is as defined above, and Q is hydrogen,—CH₂CH₂Ph-4-OSO₂CH₃ or R^(q), wherein R^(q) is as defined above, can beprepared by converting a compound of the formula XIV

wherein A is a chiral auxiliary group, —OH or —OR^(p), wherein R^(p) isas defined above, and Q is hydrogen, —CH₂CH₂Ph-4-OSO₂CH₃ or R^(q),wherein R^(q) is as defined above, with the required stereochemistry,dependent on the reaction conditions used (see for example K. Koga, C.C. Wu and S. Yamada, Tetrahedron Letters, no. 25, 1971, p 2283-2286,Kunz H., Lerchen H -G., TetrahedronLetters, 28 (17) 1987, pp.1873-1876).

G. The compound of formula II, wherein A is a chiral auxiliary group,and the compound of formula IV wherein A is a chiral auxiliary group andQ is R^(q), wherein R^(q) is as defined above, can be prepared byreacting a compound of formula XV

wherein X is a leaving group, such as a halogen or a sulfonate, and Q is—CH₂CH₂Ph-4-OSO₂CH₃ or R^(q), wherein R^(q) is as defined above, with acompound of the formula IX

wherein A is a chiral auxiliary group.

In the alkylation step the compound of formula XV is reacted with acompound of formula IX in the presence of one or more bases such aspotassium carbonate, triethylbenzyl-ammonium chloride, sodium hydride,LDA, butyllithium or LHMDS in an inert solvent such as acetonitrile, DMFor dichloromethane at a suitable temperature and time. The reaction canbe carried out using standard methods known in the literature. (see forexample Pearsson W. H., Cheng M. C., J. Org. Chem., 51 (19) 1986,3746-3748, Myers A. G., Yang B. H., Gleason J. L., J. Am. Chew Soc.1994, 116, pp 9361-9362, Negrete G. R., Konopelski J. P., TetrahedronAssymetry, 2, 2, pp. 105-108, 1991, Davies S. G., Sanganee H. J.,Tetrahedron Assymetry, 6, 3, pp. 671-674, 1995, Hulin B., Newton L. S.,Lewis D. M., Genereux P. E., Gibbs E. M., Clark D. A. J. Med.Chem. 39,3897-3907 (1996) and Savignac M., Durand J -O, Genet J -P, TetrahedronAssymetry, 5, 4, pp.717-722, 1994).

The compound of formula XV wherein X is a leaving group, such as ahalogen or a sulfonate, and Q is —CH₂CH₂Ph-4-OSO₂CH₃ or R^(q), whereinR^(q) is as defined above, can be prepared from a compound of formulaXVI

wherein Q is —CH₂CH₂Ph-4-OSO₂CH₃ or R^(q), wherein R^(q) is as definedabove, using standard methods known to anyone skilled in the art.

The compound of formula XVI wherein Q is —CH₂CH₂Ph-4-OSO₂CH₃ or R^(q),wherein R^(q) is as defined above, can be prepared by reduction of acompound of formula VIII, wherein Q is —CH₂CH₂Ph-4-OSO₂CH₃ or R^(q),wherein R^(q) is as defined above, by standard methods known to anyoneskilled in the art.

H. The compound of the invention of formula I and the compound offormula IV, wherein A is —OH and Q is hydrogen or R^(q), wherein R^(q)is as defined above, can be prepared by resolution of the racematethereof and, if desired, followed by neutralization. The resolution canbe performed by separative crystallization of a salt consisting of theracemate of, either the compound of the invention of formula I, or thecompound of formula IV, and a chiral base, such as quinine, in an inertsolvent such as ethyl acetate or toluene (see for example Duhamel P.,Duhamel L., Danvy D., Plaquevent J. C., Giros B., Gros C., Schwartz J.C., Lecomte J. M., U.S. Pat. No. 5,136,076, Stephani R., Cesare V., J.Chem. Ed., 10, 1997, p. 1226 and Yamamoto M., Hayashi M., Masaki M.,Nohira H., Tetrahedron Assymetry, 2, 6, pp. 403-406, 1991).

The compounds of the invention may be isolated from their reactionmixtures using conventional techniques.

Persons skilled in the art will appreciate that, in order to obtain thecompounds of the invention in an alternative and in some occasions, moreconvenient manner, the individual process steps mentioned hereinbeforemay be performed in different order, and/or the individual reactions maybe performed at different stage in the overall route (i.e. chemicaltransformations may be performed upon different intermediates to thoseassociated hereinbefore with a particular reaction).

In any of the preceeding methods of preparation A-H, where necessary,hydroxy, amino or other reactive groups may be protected using aprotecting group, R^(p) or R^(q) as described in the standard text“Protective groups in Organic Synthesis”, 2^(nd) Edition (1991) byGreene and Wuts. The protecting group R^(p) or R^(q) may also be aresin, such as Wang resin or 2-chlorotrityl chloride resin. Theprotection and deprotection of functional groups may take place beforeor after any of the reaction steps described hereinbefore. Protectinggroups may be removed in accordance to techniques which are well knownto those skilled in the art.

The expression “inert solvent” refers to a solvent which does not reactwith the starting materials, reagents, intermediates or products in amanner which adversely affects the yield of the desired product.

Unless otherwise stated or indicated the term chiral auxiliary groupdenotes a chiral group, such as a chiral alcohol or amine, for instance(−)-menthol, (+)-isomenthol, (−)-norneol,

(R)-2-phenyl glycinol, (S)-2-phenyl glycinol,(R)-4-phenyl-2-oxazolidinone or (S)-4-benzyl-2-oxazolidinone, which whenconnected to a carbonyl group easily can be cleaved to the correspondingacid.

Intermediates

When preparing the compound of formula I of the invention anintermediate of the formula IV

wherein Q is hydrogen and A is —OH or —OR^(p), wherein R^(p) is aprotective group, e.g. ethyl, or A is a chiral auxiliary group, such asa chiral amine, e.g. (R)-fenylglycinol, or a chiral alcohol, such asmenthol or a chiral oxazolidinone, such as(S)-4-benzyl-2-oxazolidineone, is particularly useful. It is prepared asdescribed above. Under the same heading its use as intermediate for thepreparation of the end compound of the invention is described.

Pharmaceutical Preparations

The compound of the invention will normally be administered via theoral, parenteral, intravenous, buccal, rectal, vaginal, transdemaland/or nasal route and/or via inhalation, in the form of pharmaceuticalpreparations comprising the active ingredient either as a free acid, ora pharmaceutical acceptable organic or inorganic base addition salt, ina pharmaceutically acceptable dosage form. Depending upon the disorderand patient to be treated and the route of administration, thecompositions may be administered at varying doses.

The compound of the invention may also be combined with othertherapeutic agents which are useful in the treatment of disordersassociated with the development and progress of atherosclerosis such ashypertension, hyperlipidemias, dyslipidemias, diabetes and obesity.

Suitable daily doses of the compound of the invention in therapeuticaltreatment of humans are about 0.005-5 mg/kg body weight, preferably0.01-0.5 mg/kg body weight.

According to a further aspect of the invention there is thus provided apharmaceutical formulation including the compound of the invention, orpharmaceutically acceptable derivatives thereof, in optional admixturewith pharmaceutically acceptable adjuvants, diluents and/or carriers.

Pharmacological Properties

The present compound of formula (I) will be adapted for prophylaxisand/or treatment of clinical conditions associated with reducedsensitivity to insulin (insulin resistance) and associated metabolicdisorders. These clinical conditions will include, but will not belimited to, abdominal obesity, arterial hypertension, hyperinsulinaemia,hyperglycaemia (non insulin dependent diabetes mellitus (NIDDM)) and thedyslipidaemia (plasma lipoprotein disturbances) characteristicallyappearing with insulin resistance. This dyslipidaemia, also known as theatherogenic lipoprotein profile of phenotype B, is characterised bymoderately elevated non-esterified fatty acids, elevated very lowdensity lipoproteins (VLDL) triglycerides, low high density lipoproteins(HDL) cholesterol and the presence of small, dense, low densitylipoproteins (LDL). Treatment with the present compound is expected tolower the cardiovascular morbidity and mortality associated withatherosclerosis. These cardiovascular disease conditions includemacro-angiophaties causing myocardial infarction, cerebrovasculardisease and peripheral arterial insufficiency of the lower extremities.Because of their insulin sensitizing effect the compound of formula (I)is also expected to reduce the progress of clinical conditionsassociated with chronic hyperglycaemia in diabetes like themicro-angiophaties causing renal disease and retinal damage. Furthermorethe compound may be useful in treatment of various conditions outsidethe cardiovascular system associated with insulin resistance like thepolycystic ovarian syndrome. The compound of the invention is anon-toxic insulin sensitizing agent with surprisingly good therapeuticeffect and pharmacokinetic properties and without undesirable weightgain.

General Experimental Procedures

¹H NMR and ¹³C NMR measurements were performed on a BRUKER ACP 300 andVarian UNITY plus 400 and 500 spectrometers, operating at ¹H frequenciesof 300, 400 and 500 MHz respectively, and at ¹³C frequencies of 75, 100and 125 MHz respectively.

Unless otherwise stated, chemical shifts are given in ppm with thesolvent as internal standard.

WORKING EXAMPLES Example 1

(S)-2-Ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid

a) 2-(4-Methanesulfonyloxyphenyl)ethyhlmethanesulfonate

p-Hydroxyphenethylalcohole (15 g; 0.108 mole) was dissolved indichloromethane. Triethylamine (27.3 g; 0.27 mole) was added followed byaddition of a solution of methanesulfonyl chloride (27.2 g; 0.239 mole)in dichloromethane at 0° C. The reaction mixture was allowed to reachroom temperature, then stirred at room temperature and followed by TLC.The reaction mixture was filtered and the filtrate was washed withwater. The organic phase was dried with sodium sulfate and thenevaporated in vacuo to give 28 g (yield 88%) of2-(4-methanesulfonyloxyphenyl)ethylmethanesulfonate.

¹H-NMR (400 MHz; CDCl₃): δ 2.85 (s, 3H), 3.05 (t, 2H), 3.15 (s, 3H),4.35 (s, 2H), 7.2 (dm, 2H), 7.25 (dm, 2H).

¹³C-NMR (100 MHz; CDCl₃): δ 34.8, 37, 27, 37, 31, 69.6, 122.2, 130.5,135.8, 148.1.

b) 4-[2-(4-Formylphenoxy)ethyl]phenylmethanesulfonate

2-(4-Methanesulfonyloxypheny)ethylmethanesulfonate (30 g; 0.102 mole)was dissolved in acetonitrile and slowly added to a mixture ofp-hydroxybenzaldehyde (31.1 g; 0.255 mole) and potassium carbonate(41.46 g; 0.3 mole) in acetonitrile. The resulting mixture was refluxeduntil 2-(4-methanesulfonyloxyphenyl)ethylmethanesulfonate was consumed.The salts were filtered off, the solvent evaporated in vacuo,dichloromethane was added and the organic phase was washed with water.After evaporation of the solvent, purification by chromatography onsilica gel using dichloromethane as eluant gave 21.6 g (yield 66%) of4-[2-(4-formylphenoxy)ethyl]phenylmethanesulfonate.

¹H-NMR (400 MHz; CDCl₃): δ 3.05-3.15 (t, 2H+s, 3H), 4.2 (t, 2H), 6.95(dm, 2H), 7.2 (dm, 2H), 7.3 (dm, 2H), 7.8 (dm, 2H), 9.8 (s, 1H).

¹³C-NMR (100 MHz; CDCl₃): δ 37.3, 38.3, 63.4, 116.1, 122.1, 129.2,130.6, 132.6, 138.1, 147.7, 162.6, 191.7.

c) 2-Ethoxy-3-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl}acrylicacid ethyl ester

Tetramethylguanidine (9 g; 78 mmole) was slowly added to a solution of4-[2-(4-formylphenoxy)ethyl]phenylmethanesulfonate (27 g; 84.2 mmole)and (1,2-diethoxy-2-oxyethyl)triphenylphosphonium chloride (30 g; 72mmole) in chloroform (300 ml) at 0° C. After stirring at roomtemperature over night the solvent was evaporated in vacuo. Diethylether was added to the residue and insoluble material was filtered off.More diethyl ether was added and the mixture was filtered again. Thefiltrate was washed with sodium hydrogen carbonate solution. The organicphase was dried (magnesium sulfate) and the solvent was evaporated.Recrystallilation of the residue in ethanol gave 20.2 g (yield 64.6%) of2-ethoxy-3-{4-[2-(4-methanesulfonyloxyphenyl)-ethoxy]phenyl}acrylic acidethyl ester.

¹H-NMR (500 MHz; CDCl₃): δ 1.34-1.38 (2t, 2×6H, J=7 Hz for both), 3.11(t, 2H, J=6 Hz), 3.13 (s, 3H), 3.98 (q, 2H, J=7 Hz), 4.2 (t, 2H, J=6.8Hz), 4.28 (q, 2H, J=7 Hz), 6.87 (dm, 2H, J=9 Hz, unresolved), 6.95 (s,1H), 7.23 (dm, 2H, J=9 Hz, unresolved), 7.33 (dm, 2H, J=9 Hz,unresolved), 7.73 (dm, 2H, J=9 Hz, unresolved).

¹³C-NMR (125 MHz; CDCl₃): δ 14.3, 15.5, 35.0, 37.3, 61.0, 67.5, 68.1,114.4, 122.0, 123.8, 126.6, 130.5, 131.7, 137.7, 143.1, 147.9, 159.0,164.9.

d) 2-Ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid ethyl ester

2-Ethoxy-3-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl}acrylic acidethyl ester (1.47 g; 3.38 mmole) was hydrogenated for 3 hours atatmospheric pressure in ethyl acetate (50 ml) using Pd/C (5%; 0.75 g) ascatalyst. The reaction mixture was filtered through celite and dried(magnesium sulfate). The solvent was evaporated in vacuo to give (1.44g; yield 98%) of2-ethoxy-3-[4(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoicacid ethyl ester.

¹H-NMR (500 MHz; CDCl₃): δ 1.16 (t, 3H, J=7 Hz),1.23 (t, 3H, J=7 Hz),2.92-2.96 (m, 2H), 3.09 (t, 2H, J=6.6), 3.13 (s, 3H), 3.31-3.38 (m, 1H),3.56-3.63 (m, 1H), 3.94-3.98 (m, 1H), 4.12-4.19 (m, 4H), 6.8 (dm, 2H,J=8.8 Hz, unresolved), 7.14 (dm, 2H, J=8.9 Hz, unresolved), 7.22 (dm,2H, J=8.9 Hz, unresolved), 7.33 (dm, 2H, J=8.6 Hz, unresolved).

¹³C-NMR (125 MHz; CDCl₃): δ 14.2, 15.0, 35.1, 37.2, 38.4, 60.7, 66.1,68.1, 80.3, 114.3, 121.9, 129.5, 130.4, 130.5, 138.0, 147.8, 157.4,172.5.

e) 2-Ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid

Lithium hydroxide hydrate (0.12 g; 2.82 mmole) dissolved in water (10ml) was slowly added to a solution of2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid ethyl ester (1.12 g; 2.56 mmole) in tetrahydrofuran (30 ml). Afterstirring at room temperature for 3 hours, water (50 ml) was added andtetrahydrofuran was removed by evaporation in vacuo. The water residuewas acidified with hydrochloric acid (2 M) and extracted three timeswith ethyl acetate. The organic phase was dried (magnesium sulfate),filtered and the solvent was evaporated in vacuo to give 1 g (yield 96%)of 2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)-phenyl]propanoicacid.

¹H-NMR (500 MHz; CDCl₃): δ 1.17 (t, 3H, J=7 Hz), 2.91-2.99 (m, 1H),3.03-3.11 (m, 3H), 3.12 (s, 3H), 3.39-3.47 (m, 1H), 3.57-3.64 (m, 1H),4.01-4.06 (m, 1H), 4.14 (t, 2H, J=6.7 Hz), 6.81 (dm, 2H, J=8.6 Hz,unresolved), 7.15 (dm, 2H, J=8.6 Hz, unresolved), 7.22 (dm, 2H, J=8.6Hz, unresolved), 7.33 (dm, 2H, J=8.6 Hz, uresolved).

¹³C-NMR (125 MHz; CDCl₃): δ 15.0, 35.1, 37.2, 37.8, 66.8, 68.1, 79.7,114.4, 121.9, 128.8, 130.49, 130.52, 137.9, 147.8, 157.5, 169.1.

f)(S)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoicamide.

A solution of2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoicacid (10.5 g; 25.7 mmole) in dry dichloromethane (150 ml) was cooled onan ice-bath and EDC (5.42 g; 28.3 mmole), diisopropylethylamine (4.8 ml;28.3 mmole) and HOBtxH₂O (3.82 g; 28.3 mmole) were added. After 20minutes the ice-bath was removed and (R)-phenylglycinol (3.88 g; 28.3mmole) was added. After stirring at room temperature over nightdichloromethane (100 ml), citric acid (60 ml, 10%) and ethyl acetatewere added and the phases were separated. The organic phase was washedwith citric acid (60 ml), sodium bicarbonate (2×60 ml) and brine (60ml), dried (sodium sulfate), filtered and the solvent evaporated invacuo. The crude product was crystallized twice in ethyl acetate/heptanto give 4.43 g of(R)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoicamide. The mother liquids were combined, the solvent was evaporated invacuo and the residue was purified by chromatography on silica gel usingethyl acetate:heptan (gradient 25 to 100% ethyl acetate) to give 5.14 g(yield 38%)of(S)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)-phenyl]propanoicamide and 0.51 g (totally 4.94 g, yield 36%) of(R)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoicamide.

¹H-NMR (600 MHz; DMSO-d₆): δ 1.04 (t, 3H, J=7.0 Hz), 2.74 (dd, 1H,J=13.9 and 7.6 Hz), 2.84 (dd, 1H, J=13.9 and 5.3 Hz), 3.05 (t, 2H, J=6.7Hz), 3.30 (m, 1H), 3.34 (s, 3H), 3.44 (m, 1H), 3.55 (t, 2H, J=5.8 Hz),3.88 (dd, 1H, J=7.3 and 5.5 Hz), 4.15 (t, 2H, J=6.7 Hz), 4.83 (m, 1H),4.85 (t, 1 OH, J=5.4 Hz), 6.80 (d, 2H, J=8.4 Hz), 7.09 (d, 2H, J=8.4Hz), 7.17 (m, 3H), 7.23 (m, 2H), 7.28 (d, 2H, J=8.3 Hz), 7.43 (d, 2H,J=8.3 Hz), 8.06 (d, 1 NH, J=8.2 Hz).

¹³C-NMR (150 MHz; DMSO-d₆): δ 15.2, 34.4, 37.5, 38.0, 54.6, 64.5, 65.1,67.9, 81.1, 114.2, 122.2, 126.8, 127.0, 128.1, 129.8, 130.4, 130.7,138.1, 141.2, 147.8, 157.0, 171.1.

g)(S)-2-Ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid

(S)-2-Ethoxy-N-(2-hydroxy(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicamide (4.49 g; 8.59 mmole), concentrated sulfuric acid (12.5 Ml), dioxan(50 ml) and water (50 ml) were stirred at 80° C. for 6 hours. Aftercooling, water (100 ml) was added and the product was extracted withdichloromethane (2×100 ml). The organic phases were combined and washedwith brine (60 ml), dried (sodium sulfate), filtered and evaporated invacuo. Purification by chromatography on silica gel using heptan:ethylacetate:acetic acid (10:10:1) as gradient and azeotropic destillationwith toluen gave 2.78 g (yield 79%) of(S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid.

¹H-NMR (600 MHz; DMSO-d₆): δ 1.02 (t, 3H, J=7.0 Hz), 2.78 (dd, 1H,J=13.9 and 8.0 Hz), 2.86 (dd, 1H, J=13.9 and 5.2 Hz), 3.04 (t, 2H, J=6.8Hz), 3.28 (dq, 1H, J32 9.1 and 7.0 Hz), 3.35 (s, 3H), 3.49 (dq, 1H,J=9.1 and 7.0 Hz), 3.92 (dd, 1H, J=5.2 and 7.7 Hz),4.15(t, 2H, J=6.8Hz), 6.82 (d, 2H, J=8.7 Hz), 7.11 (d, 2H, J=8.7 Hz), 7.27 (d, 2H, J=8.5Hz), 7.42 (d, 2H, J=8.5 Hz), 12.59 (s, br, 1 OH).

¹³C-NMR (150 MHz; DMSO-d₆): δ 15.2, 34.4, 37.5, 37.7, 65.0, 67.9, 79.4,114.2, 122.2, 129.6, 130.4, 130.7, 138.0, 147.8, 157.1, 173.4.

Example 2

(S)-2-Ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid

a) 3-(4-Benzyloxyphenyl)-2-ethoxyacrylic acid ethyl ester

Tetramethylguanidine (33 g; 0.286 mole) was added to a solution of4-benzyloxybenzaldehyde (59.1 g; 0.278 mole) and(1,2-diethoxy-2-oxyethyl) (triphenyl) phosphonium chloride (101.8 g;0.237 mole) in dichloromethane (600 ml) at 0° C. After stirring at roomtemperature over night, the solvent was evaporated in vacuo. The residuewas dissolved in diethyl ether, insoluble material was filtered off andthe filtrate was evaporated. The residue was stirred over night withsodium bisulfite (saturated water solution) and diethyl ether. The solidmaterial was filtered off, the filtrate was extracted with diethylether, dried (magnesium sulfate) and the solvent was evaporated invacuo. Purification of the crude product by flash chromatography andcrystallization in isopropanol gave 66.8 g (yield 86.3%) of3-(4-benzyloxyphenyl)-2-ethoxyacrylic acid ethyl ester.

¹³C-NMR (125 MHz; CDCl₃): δ 14.4, 15.6, 61.0, 67.5, 70.0, 114.8, 124.0,126.7, 127.5, 128.1, 128.6, 131.7, 136.7, 143.1, 159.2, 165.0.

b) 3-(4-Benzyloxyphenyl)-2-ethoxypropanoic acid ethyl ester

3-(4-Benzyloxyphenyl)-2-ethoxyacrylic acid ethyl ester (0.5 g; 1.5mmole) was hydrogenated at atmospheric pressure using rhodium oncharcoal as catalyst (5%, 50 mg) in methanol (20 ml). The crude productwas purified by chromatography using heptane:ethyl acetate (5:1) aseluant to give 50 mg (yield 10%) of3-(4-benzyloxyphenyl)-2-ethoxypropanoic acid ethyl ester.

¹H NMR (300 MHz; CDCl₃): δ 7.47-7.30 (m, 5H), 7.17 (d, J=8.8, 2H), 6.91(d, J=8.8 Hz, 2H), 5.06 (s, 2H), 4.17 (q, J=7.2 Hz, 2H), 3.98 (t, J=6.6Hz, 1H), 3.61 (dq, J=8.9 and 6.8 Hz, 1H), 3.36 (dq, J=8.9 and 6.8 Hz,1H), 2.97 (d, J=6.6 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H), 1.18 (t, J=6.8 Hz,3H).

¹³C NMR (75 MHz; CDCl₃): δ 172.6, 157.6, 137.1, 130.4, 129.5, 128.6,127.9, 127.5, 114.6, 80.4, 70.0, 66.2, 60.8, 38.5, 15.1, 14.2.

c) 3-(4-Benzyloxyphenyl)-2-ethoxypropanoic acid

Lithium hydroxide hydrate (7.4 g; 177 mmole) dissolved in water (150 ml)was added to a solution of 3-(4-benzyloxyphenyl)-2-ethoxypropanoic acidethyl ester (23.25 g; 70.8 mmole) in dioxan (150 ml). After stirring atroom temperature over night dioxan was evaporated in vacuo, water wasadded and the mixture was washed with diethyl ether. The water phase wasacidified with hydrochloric acid (1 M) and extracted with ethyl acetate.The organic phase was washed with water and brine, dried and the solventwas evaporated in vacuo to give 21.1 g (yield 99.2%) of3-(4-benzyloxyphenyl)-2-ethoxypropanoic acid.

¹H NMR (300 MHz; CDCl₃): δ 1.15 (t, 3H), 2.9-3.1 (m, 2H), 3.35-3.45 (m,1H), 3.6-3.7 (m, 1H), 3.95-3.41 (m, 1H), 5.05 (s, 2H), 6.95 (d, 2H), 7.2(d, 2H), 7.25-7.5 (m, 5H).

¹³C NMR (75 MHz; CDCl₃): δ 15.0, 38.1, 66.6, 70.0, 79.9, 114.7, 127.5,128.0, 128.6, 129.3, 130.5, 137.1, 157.7, 176.3.

d)3-(4-Benzyloxyphenyl)-(S)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)propanoicamide

A solution of 3-(4-benzyloxyphenyl)-2-ethoxypropanoic acid (2.92 g, 9.74mmole) in dry dichloromethane (30 ml) was cooled on an ice-bath and EDC(2.03g; 10.61 mmole), diisopropylethylamine (1.84 ml, 10.61 mmole) andHOBt x H₂O (1.43 g; 10.61 mmole) were added. After 30 minutes theice-bath was removed and (R)-phenylglycinol (1.46 g, 10.61 mmole) wasadded. After stirring at room temperature over night ethyl acetate (100ml) was added and the mixture was washed with potassium hydrogensulfate(1 M), saturated sodium bicarbonate solution, sodium carbonate solutionand brine. The organic phase was dried (sodium sulfate), filtered andthe solvent was evaporated in vacuo. The crude product was purified bychromatography on silica gel using ethyl acetate:heptan to give 1.5 g(yield 37%) of3-(4-benzyloxyphenyl)(S)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)propanoicamide and 1.25 g (yield 31%) of3-(4-benzyloxyphenyl)-(R)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)propanoicamide.

¹H NMR (400 MHz; CDCl₃): δ 7.43-7.27 (m, 8H), 7.22 (d, J=8.3 Hz, 4H),7.13 (d, NH, J=7.8 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 5.08 (s, 2H), 5.01(m, 1H), 3.99 (dd, J=6.8 and 3.9 Hz, 1H), 3.69 (m, 2H), 3.50 (q, J=6.8Hz, 2H), 3.15 (dd, J=14.2 and 3.9 Hz, 1H), 2.97 (dd, J=14.2 and 6.8 Hz,1H), 2.94 (m, OH, 1H), 1.16 (t, J=6.8 Hz, 3H).

¹³C NMR (100 MHz; CDCl₃): δ 172.3, 157.5, 138.9, 137.0, 130.7, 129.4,128.6, 128.4, 127.7, 127.6, 127.3, 126.5, 114.4, 81.0, 69.8, 66.3, 66.0,55.3, 37.8, 15.1.

e) 3-(4-Benzyloxyphenyl)-(S)-2-ethoxypropanoic acid

3-(4-Benzyloxyphenyl)-(S)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)propanoicamide (8.9 g; 21.22 mmole) was hydrolyzed with concentrated sulfiricacid (27 ml) in water (104 ml) and dioxane (104 ml) at 90° C. for 5hours. The reaction mixture was poured onto water (220 ml) and extractedwith ethyl acetate. The organic phase was washed with brine, dried(sodium sulfate) and the solvent was evaporated in vacuo to give 6.85 gof a mixture of 3-(4-benzyloxyphenyl)-2-(S)-ethoxypropanoic acid and(S)-2-ethoxy-3-(4-hydroxyphenyl)-propanoic acid, which was used withoutfurther purification.

¹H NMR (400 MHz; CDCl₃): δ 7.47-7.30 (m, 5H), 7.19 (d, J=8.8, 2H), 6.93(d, J=8.8 Hz, 2H), 5.10 (s, 2H), 4.06 (dd, J=7.8 and 4.4 Hz, 1H), 3.64(dq, J=9.8 and 6.8 Hz, 1H), 3.44 (dq, J=9.8 and 6.8 Hz, 1H), 3.09 (dd,J=14.2 and 4.4 Hz, 1H), 2.98 (dd, J=14.2 and 7.8 Hz, 1H), 1.19 (t, J=6.8Hz,3H).

f) 3-(4-Benzyloxyphenyl)-(S)-2-ethoxypropanoic acid ethyl ester

Hydrogen chloride (g) was bubbled through a solution of3-(4-benzyloxyphenyl)-2-(S)-ethoxypropanoic acid (6.85 g) in ethanol(460 ml). Thionyl chloride (2 ml, 27.4 mmole) was slowly added and thereaction mixture was refluxed for 2 hours. The solvent was evaporated invacuo to give 8 g of a mixture of3-(4-benzyloxyphenyl)-(S)-2-ethoxypropanoic acid ethyl ester and(S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester which wasused without flier purification.

¹H NMR (300 MHz; CDCl₃): δ 7.47-7.30 (m, 5H), 7.17 (d, J=8.8, 2H), 6.91(d, J=8.8 Hz, 2H), 5.06 (s, 2H), 4.17 (q, J=7.2 Hz, 2H), 3.98 (t, J=6.6Hz, 1H), 3.61 (dq, J=8.9 and 6.8 Hz, 1H), 3.36 (dq, J=8.9 and 6.8 Hz,1H), 2.97 (d, J=6.6 Hz, 2H),1.22(t, J=7.2 Hz, 3H), 1.18 (t, J=6.8 Hz,3H).

¹³C NMR (75 MH; CDCl₃): δ 172.6, 157.6, 137.1, 130.4, 129.5, 128.6,127.9, 127.5, 114.6, 80.4, 70.0, 66.2, 60.8, 38.5, 15.1, 14.2.

g) (S)-2-Ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester

3-(4-Benzyloxyphenyl)-(S)-2-ethoxypropanoic acid ethyl ester washydrogenated at atmospheric pressure for 2 hours in ethyl acetate usingPd/C as catalyst. Purification by chromatography on silica gel usingtoluen:ethyl acetate as eluant gave 3.83 g (yield in 3 steps 76%) of(S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester.

¹H-NMR (400; CDCl₃); δ 1.18 (t, 3H, J=6.8 Hz), 1.24 (t, 3H, J=7 Hz),2.96 (d, 2H, J=6.5 Hz), 3.34-3.43 (m, 1H), 3.57-3.66 (mn, 1H), 4.00 (t,1H, 6.5 Hz), 4.18 (q, 2H, J=7 Hz), 5.30 (s, 1 OH), 6.74 (dm, 2H, J=8.5Hz, unresolved), 7.10 (dm, 2H, J=8.5 Hz, unresolved).

¹³C-NMR (100 MHz; CDCl₃): δ 14.2, 15.0, 38.4, 60.9, 66.2, 80.4, 115.1,129.0, 130.5, 154.5, 172.7.

h)(S)-2-Ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid ethyl ester

A solution of 2-(4-methanesulfonyloxyphenyl)ethylmethanesulfonate(described in Example 1a) (2.41 g; 8.14 mmole) in acetonitrile (11.8 ml)was added to a mixture of (S)-2-ethoxy-3-(4-hydroxyphenyl) propanoicacid ethyl ester (1.3 g; 5.46 mmole), potassium carbonate (2.26 g; 16.4mmole) and magnesium sulfate (1 g) in acetonitrile (50 ml). The reactionmixture was refluxed for 19 hours. More of2-(4-methanesulfonyloxyphenyl)ethyl-methanesulfonate (0.8 g; 2.73 mmole)was added and the reaction mixture was refluxed for another 25 hours.Solid material was filtered off and the solvent was evaporated in vacuoto give 3.6 g of(S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]-propanoicacid ethyl ester.

i)(S)-2-Ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid

Lithium hydroxide hydrate (0.229 g; 5.45 mmole) dissolved in water (6ml) was slowly added to a mixture of(S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]-propanoicacid ethyl ester (2.29 g; 5.24 mmole) in tetrahydrofuran (50 ml) andwater (10 ml) at 5° C. The reaction mixture was stirred at 5° C. for 2.5hours, at 20° C. for 3 hours, at 0° C. for 15 hours and at 20° C. for3,5 hours. More lithium hydroxide hydrate (44 mg, 1.05 mmole) dissolvedin water (1 ml) was added at 10° C. After another 21.5 hours of stirringat 10° C., more lithium hydroxide hydrate (44 mg; 1.05 mmole) dissolvedin water (1 ml) was added. The reaction mixture was stirred at 25° C.for 3 hours and then kept at 2° C. for 67 hours. Tetrahydrofuran wasevaporated in vacuo and then water and ethyl acetate were added.Insoluble material was filtered off and the phases of the filtrate wereseparated. The water phase was washed twice with ethyl acetate,acidified with hydrochloric acid (2 M; 3.2 ml) and extracted with ethylacetate (30 ml). The organic phase was washed twice with water, dried(magnesium sulfate), filtered and the solvent was evaporated in vacuo togive 1.9 g (yield 72% in 2 steps)of(S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoicacid.

¹H-NMR (600 MHz; DMSO-d₆): δ 1.02 (t, 3H, J=7.0 Hz), 2.78 (dd, 1H,J=13.9 and 8.0 Hz), 2.86 (dd, 1H, J=13.9 and 5.2 Hz), 3.04 (t, 2H, J=6.8Hz), 3.28 (dq, 1H, J=9.1 and 7.0 Hz), 3.35 (s, 3H), 3.49 (dq, 1H, J=9.1and 7.0 Hz), 3.92 (dd, 1H, J=5.2 and 7.7 Hz), 4.15 (t, 2H, J=6.8 Hz),6.82 (d, 2H, J=8.7 Hz), 7.11 (d, 2H, J=8.7 Hz), 7.27 (d, 2H, J=8 .5 Hz),7.42 (d, 2H, J=8.5 Hz), 12.59 (s, br, 1 OH).

¹³C-NMR (150 MHz; DMSO-d₆): δ 15.2, 34.4, 37.5, 37.7, 65.0, 67.9, 79.4,114.2, 122.2, 129.6, 130.4, 130.7, 138.0, 147.8, 157.1, 173.4.

Biological Activity

The biological activity of the compound of the invention was tested inobese diabetic mice of the Umeå ob/ob strain. Groups of mice receivedthe test compound by gavage once daily for 7 days. On the last day ofthe experiment the animals were anesthetized 2 h after dose in a non-fedstate and blood was collected from an incised artery. Plasma wasanalyzed for concentration of glucose, insulin and triglycerides. Agroup of untreated obese diabetic mice of the same age served ascontrol. The weight of the mice was measured before and after theexperiment and the obtained weight gain was compared to the weight gainof the control animals. The individual values for glucose, insulin andtriglyceride levels of the mice from the test group were expressed asthe percent rage of the corresponding values from the control group.

The desired “therapeutic effect” was calculated as the average percentreduction of the three variables glucose, insulin and triglyceridesbelow the levels in the control animals. The therapeutic effect of thetested compounds according to the invention was compared to the sameeffect in the prior art compound troglitazone, administered by gavage inthe oral dose of 100 μmol/kg for 7 days.

The superior effects of the tested compound according to the inventioncompared to that of troglitazone when given in the same oral dosedemonstrate the increased potency and efficiacy of the claimed compound.

Abbreviations NIDDM non insulin dependent diabetes mellitus VLDL verylow density lipoproteins HDL high density lipoproteins IRS insulinresistance syndrom PPAR peroxisome proliferator activated receptor DEADdiethyl azodicarboxylate ADDP azodicarbonyl dipiperidine EDC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDCxHCl1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride DCCdicyclohexylcarbodiimide HBTUO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphateTBTU O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroboratePyBop benzotriazole-1-yl-oxy-tris-pyrolidino-phosphoniumhexafluorophosphate DMF dimethylformamide DMAP 4-dimethylaminopyridineTEA triethylamine DiPEA diisopropylethylamine BINAP2,2′-bis(diphenylphosphino)-1,1′-binaphtyl COD cyclooctadiene LDAlithium diisopropylamide LHMDS lithium hexamethyldisilylamine TLC thinlayer chromatography THF tetrahydrofuran Pd/C palladium on charcoalHOBtxH2O 1-hydroxybenzotriazole-hydrate m multiplet t triplet s singletd doublet q quartet qvint quintet br broad dm multiplet of doublet racracemate

What is claimed is:
 1. A compound having the formula

or a pharmaceutically acceptable salt, solvate or crystalline formthereof.
 2. A process for the preparation of a compound according toclaim 1, comprising the steps of a) converting a compound of the formulaII

wherein A is a chiral auxiliary group or the group —OR^(p), whereinR^(p) is a protective group, or b) reacting a compound of the formulaIII

with a compound of the formula IV

in which formulas A is —OH, a chiral auxiliary group or the group—OR^(p), wherein R^(p) is a protective group, X is —OH or a leavinggroup and Q is H, whereafter, if necessary, hydrolysing the obtainedcompound, or c) diastereoisomerically separating a compound of theformula V

wherein Q is —CH₂CH₂Ph-4-OSO₂CH₃ and A is a chiral auxiliary group,whereafter hydrolysing the obtained compound, or d) enantiomericallyseparating a compound of the formula V

wherein Q is —CH₂CH₂Ph-4-OSO₂CH₃ and A is —OH or —OR^(p), wherein R^(p)is a protective group, whereafter, if necessary hydrolysing the obtainedcompound, or e) asymmetrically reducing a compound of the formula VII

wherein Q is —CH₂CH₂Ph-4-OSO₂CH₃ and A is —OH, a chiral auxiliary groupor the group —OR^(p), wherein R^(p) is a protective group, whereafter,if necessary, hydrolysing the obtained compound, or f) alkylating acompound of the formula XII

wherein Q is —CH₂CH₂Ph-4-OSO₂CH₃ and A is —OH, a chiral auxiliary groupor the group —OR^(p), wherein R^(p) is a protective group, whereafter,if necessary, hydrolysing the obtained compound, or g) reacting acompound of the formula XV

with a compound of the formula IX

in which formulas X is a leaving group, Q is —CH₂CH₂Ph-4-OSO₂CH₃ and Ais a chiral auxiliary group used to induce chirality in the productwhereafter, hydrolysing the obtained compound, or h) resolving aracemate of the formula I^(rac)

whereafter, optionally, the compound obtained according to any ofmethods a)-h) is converted to a pharmaceutically acceptable salt, and/ora solvate thereof.
 3. A pharmaceutical formulation comprising a compoundaccording to claim 1 as active ingredient and optionally a substanceselected from the group consisting of a pharmaceutically acceptablecarrier, adjuvant, diluent and mixtures thereof.
 4. A method for theprophylaxis and/or treatment of clinical conditions associated withinsulin resistance wherein a therapeutically active amount of a compoundaccording to claim 1 is administered to a mammal in need of suchprophylaxis and/or treatment.
 5. The method according to claim 4 whereinthe prophylaxis and/or treatment of clinical conditions associated withinsulin resistance is the prophylaxis and/or treatment of dyslipidaemia.6. The method according to claim 4 wherein the prophylaxis and/ortreatment of clinical conditions associated with insulin resistance isthe prophylaxis and/or treatment of hyperglycaemia in non insulindependent diabetes mellitus.
 7. A pharmaceutical formulation for theprophylaxis and/or treatment of clinical conditions associated withinsulin resistance wherein the active ingredient is a compound accordingto claim
 1. 8.(S)-2-Ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid.